Genomic, epigenomic and systems dissection of mechanisms underlying dilated cardiomyopathy

• Stuart COOK, Imperial College, London (UK)

• Christine SEIDMAN, Harvard Medical School, Boston (USA)

Dilated cardiomyopathy (DCM) represents a group of diseases of the heart muscle in which the heart becomes enlarged and weakened. It is the most common cause of heart failure after ischemic cardiomyopathy, where there is heart muscle dysfunction because of an inadequate blood supply, such as with coronary artery disease. Despite the clinical importance of DCM, the molecular basis of DCM remains poorly understood.

This network will apply state-of-the-art techniques to determine the genetic and mechanistic pathways of DCM. The investigators will identify genetic mutations in patients with DCM using both genome-wide association approaches and the latest DNA sequencing techniques; early results from such efforts have already uncovered a wealth of new information. The network will then determine the mechanisms by which the identified mutations cause DCM in fruit fly, zebrafish, mouse and rat models, and in human heart tissue. These studies will include the effects of the mutations on physiologic parameters like muscle cell contractility and electrical stability.

It is known that two patients with the same genetic mutation may have very different manifestations of DCM. For this reason, the network will also study differences in gene expression patterns caused by mechanisms other than changes in the DNA (epigenetics). In summary, this network brings together world-class investigators with well-characterized patient cohorts, large DNA and tissue repositories, and expertise in genomics, cross-species models, and systems-level informatics to address a challenging clinical problem. Ultimately, the investigators hope that their findings in DCM will provide important mechanistic and therapeutic insight for all causes of heart failure.